Our proposal addresses NCI's Provocative Question #3 (Group A): We designed a strategy to change cancer- inducing dietary habits, which is based on rescuing normal neural activity in brain circuits of overweight/obese individuals. The relevance of our proposal to cancer prevention is demonstrated by epidemiological studies establishing that several forms of cancer could be prevented by the adoption of healthier dietary habits, with up to 20% of cancer-related deaths being potentially attributable to obesity alone. In both rodents and humans, excessive intake of dietary fats leads to dysregulated neuronal function in dorsal striatum. This diet-derived striatal deficiency leads to an impaired ability to learn about the negative outcomes of one's actions which, in turn, results in the expression of impulsive behaviors such as excessive caloric intake. Our strategy builds on previous animal studies demonstrating that prolonged exposure to a high-fat diet substantially reduces the intestinal synthesis of appetite-regulating lipid messengers. Since our previous work had established that gut- brain signals regulate neurochemical activity in dorsal striatum, we set fort the central hypothesis that rescuing gut-brain communication will restore striatal function. As a corollary, we predict that rescuing gut-brain communication will enhance the ability to learn about negative outcomes, thereby reducing impulsivity behavioral scores and increasing compliance with a low-calorie diet. Accordingly, our Specific Aims are as follows: Specific Aim 1 (Mechanistic studies): To identify which gut N-acylethanolamines rescue striatal function and reduce impulsivity in high-fat fed mice, and to determine the neural and molecular mechanisms of their action; Specific Aim 2 (Translational studies): To determine whether gut N-Acylethanolamines precursors rescue striatal function and reduce impulsivity scores in overweight/obese human subjects. We thus propose that the gut-brain axis is a novel target for treating behavioral alterations in the obese, the normalization of which may greatly contribute to reducing cancer-related dietary habits.